The transcription factor EGR2 is indispensable for tissue-specific imprinting of alveolar macrophages in health and tissue repair

Abstract

EGR2 controls alveolar macrophage function in health and disease.

The impact of the lung environment on macrophage development, activation and function: diversity in the face of adversity

“…Consequently, genetic disruption of Itgb6 , which encodes integrin β6, leads to development of emphysema due to excessive production of MMP12 by dysfunctional AlvMϕs; a phenotype that can be rescued by constitutive expression of TGFβ1 121 , 122 . Human AMϕs are known to have a gene signature consistent with TGFβR signalling 123 and myeloid-specific deletion of TGFβR in mice leads to aborted AlvMϕ development, demonstrating a need for cell intrinsic TGFβR for this process 124 , 125 . Interestingly, although many cells can produce TGFβ, macrophages themselves are thought to be an important source 123 , 124 .…”

“…Given that PPARγ is expressed by macrophages in other tissues, including splenic red pulp macrophages and macrophages of the erythroblastic islands in the bone marrow 129 , 130 , until recently, it remained unclear how specificity was conferred to AlvMϕs. We recently uncovered the transcription factor early growth response 2 (EGR2) as a key evolutionarily conserved regulator of AlvMϕ differentiation downstream of PPARγ in the lung but not spleen 125 . Interestingly, mice with Egr2 deficient AlvMϕs and individuals with mutations in EGR2 do not appear to develop spontaneous PAP 125 , 131 , demonstrating that PPARγ must cooperate with other transcriptional regulators to regulate distinct aspects of AlvMϕ biology.…”

“…We recently uncovered the transcription factor early growth response 2 (EGR2) as a key evolutionarily conserved regulator of AlvMϕ differentiation downstream of PPARγ in the lung but not spleen 125 . Interestingly, mice with Egr2 deficient AlvMϕs and individuals with mutations in EGR2 do not appear to develop spontaneous PAP 125 , 131 , demonstrating that PPARγ must cooperate with other transcriptional regulators to regulate distinct aspects of AlvMϕ biology. For instance, EGR2 appears particularly important for regulating expression of adhesion molecules, chemotactic machinery and apparatus for the detection and elimination of respiratory pathogens 125 .…”

“…Interestingly, mice with Egr2 deficient AlvMϕs and individuals with mutations in EGR2 do not appear to develop spontaneous PAP 125 , 131 , demonstrating that PPARγ must cooperate with other transcriptional regulators to regulate distinct aspects of AlvMϕ biology. For instance, EGR2 appears particularly important for regulating expression of adhesion molecules, chemotactic machinery and apparatus for the detection and elimination of respiratory pathogens 125 . EGR2 appears to maintain expression of CCAAT/enhancer-binding protein beta (C/EBPβ), which has been implicated in AlvMϕ differentiation 132 .…”

“…The downstream molecular pathways that govern IntMϕ differentiation remain largely elusive. Although expression of Maf, Mafb, Irf5, Jun and Atf3 have been identified through scRNA-seq studies as highly expressed by murine IntMϕs 6 , 125 , if and how these transcription factors control their differentiation remains unexplored. Furthermore, given that some of these (e.g., IRF5) have been implicated in AlvMϕ homeostasis 140 , high expression does not always equate to specificity.…”